Does the Hazard of Chlamydia Increase with the Number of Gonorrhea Diagnoses? A Large Population-Based Study Among U.S. Army Women

Abstract

Background:

In the U.S. military, chlamydia and gonorrhea are common sexually transmitted infections, especially among female service members. The aim of this study was to determine whether the number of gonorrhea diagnoses sustained an increased hazard of chlamydia among military women.

Methods:

This population-based study involved an analysis of all female gonorrhea cases in the U.S. Army reported in the Defense Medical Surveillance System between 2006 and 2012. The effect of the number of gonorrhea diagnoses on the hazard of chlamydia was analyzed using the Prentice-Williams-Peterson gap-time model.

Results:

Among 3,618 women with gonorrhea diagnosis, 702 (19.4%) had a subsequent chlamydia diagnosis yielding a rate of 6.06 (95% CI = 5.63–6.53) cases per 100 person-years. Compared to women with one gonorrhea diagnosis, the hazard ratio of chlamydia for women with two gonorrhea diagnoses was 5.09 (95% CI = 4.42–5.86) and for women with three gonorrhea diagnoses was 6.53 (95% CI = 3.93–10.83). The median time to chlamydia diagnosis decreased from 2.39 to 0.67 years for women with two to three gonorrhea diagnoses.

Conclusions:

The hazard of chlamydia increased significantly with the number of gonorrhea diagnoses and the median time to chlamydia diagnosis decreased with an increasing number of gonorrhea diagnoses among U.S. Army women.

Introduction

Chlamydia and gonorrhea are the most common bacterial sexually transmitted infections (STIs) in the U.S. military, a population predominantly young, sexually active men and women.¹ According to surveillance military data, 198,274 chlamydia and 41,713 gonorrhea diagnoses were reported among service members during 2000–2012.¹ Of these, the largest number of diagnoses for both STIs occurred among U.S. Army personnel, female personnel, and service members younger than 25 years. Surveillance data also indicate that there has been an increase in the number of chlamydia diagnoses among female service members since 2000.¹

In the field of STIs, subjects with repeat infections, also called “repeaters”, represent a sustained reservoir of infection for transmission within their sexual networks.² In addition, repeaters are at greater risk of having complications or adverse reproductive health outcomes such as pelvic inflammatory disease, which may lead to ectopic pregnancy or tubal factor infertility in women, and testicular damage and infertility in men.^3,4 Recently, Owings et al.⁵ reported that among 1,816 female service members with gonorrhea during 2010–2014, 206 (11%) of them had a repeat diagnosis. This estimate was slightly higher compared to the U.S. civilian population based on case-based surveillance systems (9.7%).⁶ The U.S. Army has no policy for gonorrhea screening at the time of entry into the military or during service.

Several studies have reported a relationship between a recent history of gonorrhea and repeat diagnoses with chlamydia among females.⁶ However, we were not aware of studies that have determined the risk of chlamydia after certain number of gonorrhea diagnoses. This is, in part, due to the lack of data from large cohort studies with long follow-up periods, which are very expensive and time-consuming. One approach to estimating the risk is to analyze large epidemiologic and clinical databases from existing surveillance systems, such as the Defense Medical Surveillance System (DMSS).⁷

The aim of this study was to determine whether the number of gonorrhea diagnoses increased the hazard of chlamydia among U.S. Army women using data from the DMSS.

Methods

Data source

This population-based study used medical diagnostic information of U.S. Army female service members registered into the DMSS. DMSS is a large relational database, which serves as the central health surveillance system for monitoring the health of the U.S. Armed Forces since 1993.⁷ The database includes information on demographics, reportable diseases, deployments, all inpatient and outpatient healthcare provider (HCP), and laboratory-based diagnoses among military personnel from the day they enter service until the day they leave.

Study design and population

For this study, the outcome of interest was the first genital chlamydia diagnosis recorded in the DMSS among U.S. Army women with one or more gonorrhea diagnoses. The study population consisted of all females who had at least one gonorrhea diagnosis in the DMSS database between January 1, 2006, and December 31, 2012. For both STIs, the case definition was based on the International Classification of Diseases, version 9 (ICD-9) diagnosis codes reported by an HCP in any outpatient or inpatient visit in either the first or the second diagnostic position. For chlamydia, the codes were 099.41 or 099.5x (rectal infections were excluded), and for gonorrhea, the codes were 098.0x, 098.1x, or 098.8x.

Medical records were then reviewed to determine the number of gonorrhea diagnoses until one of three censoring events: (1) end of the study period; (2) termination of military service; or (3) a diagnosis of chlamydia. Given that the nucleic acid amplification tests can detect residual bacterial deoxyribonucleic acid for up to 3 weeks after STI therapy,⁸ for analysis, a new gonorrhea diagnosis was defined as one, which occurred a minimum of 30 days after the previous diagnosis. This definition is also consistent with CDC guidance.⁹ In addition, all women with a prior diagnosis of chlamydia were excluded from analysis.

Study variables

Demographic variables, including age, race/ethnicity (white, African American, or other), educational level (high school, college, or higher), marital status (single, married, or other), and military rank (officer, senior enlisted, or junior enlisted), were extracted from the DMSS. To examine whether the history of other infections had an effect in the association between the number of gonorrhea diagnoses and the hazard of chlamydia, we also searched the DMSS database for diagnoses of bacterial vaginosis (616.10), genital herpes simplex virus (054.1), and trichomoniasis (131.9), which occurred before the initial gonorrhea diagnosis using their ICD-9 diagnosis codes.

Statistical analysis

The incidence rate for chlamydia was calculated by dividing the number of new diagnoses by the person-time of the study population (women with one or more gonorrhea diagnoses). This same approach was used to obtain the rates of chlamydia stratified by repeat gonorrhea diagnosis, but the person-time was calculated as the number of days between the first (initial) diagnosis and the second diagnosis or a censoring occurred, and then between the second and third diagnosis or a censoring occurred. All rates were expressed per 100 person-years.

To estimate the association between chlamydia and the number of gonorrhea diagnoses, the Prentice-Williams-Peterson gap-time model (PWP-GT) was applied.¹⁰ This conditional marginal Cox-type model considers that the hazard varies with recurrence number, and thus, analysis data by stratifying the number of diagnosis. In our study, the first group of women included all women who had one gonorrhea diagnosis or were censored without a new diagnosis. The second group included women who had two gonorrhea diagnoses or were censored after the first gonorrhea diagnosis, whereas, the third group of women included only those women who had three gonorrhea diagnoses or were censored after the second gonorrhea diagnosis. The association of chlamydia was expressed as hazard ratios (HR). The proportional-hazards assumption was evaluated using the Global test.¹¹ All analyses were conducted using Stata version 12 (Stata Corporation, College Station, TX).

Ethical approval

The study was approved by scientific review and institutional review boards at Lancaster University and the Walter Reed Army Institute of Research.

Results

Characteristics of gonorrhea cases

During the study period, 4,987 women with an initial gonorrhea diagnosis were identified from the DMSS. Of these, 1,369 (27%) were excluded because of a prior diagnosis of chlamydia. Among the 3,618 eligible women, 77% were aged 17–24 years (mean = 22.6 years at the time of diagnosis), 56% were African Americans, 68% were single, 84% were junior enlisted members, and most (90%) had a high school diploma (Table 1). Also, 1, 3, and 33 of the eligible women had a prior diagnosis of genital herpes simplex virus, trichomoniasis, and bacterial vaginosis, respectively. Among 3,618 women, 310 (9%) had a second gonorrhea diagnosis. Of these 310 women, 29 (9%) had a third gonorrhea diagnosis. Selected demographic and military characteristics of these subgroups of women are shown in Table 1.

Table 1.

Selected Demographic and Military Characteristics of the Study Population

Feature	Women with one gonorrhea diagnosis n (%)	Women with two gonorrhea diagnoses n (%)	Women with three gonorrhea diagnoses n (%)
No. of women	3,618 (100.0)	310 (100.0)	29 (100.0)
Age group (years)
17–19	919 (25.4)	72 (23.2)	8 (30.8)
20–24	1,879 (51.9)	177 (57.1)	14 (53.8)
≥25	820 (22.7)	61 (19.7)	4 (15.4)
Race/ethnicity
White	877 (24.7)	72 (23.8)	6 (23.1)
African American	1,995 (56.2)	192 (63.3)	18 (69.2)
Other^a	675 (19.1)	39 (12.9)	2 (7.7)
Marital status
Single	2,454 (67.9)	205 (66.8)	19 (73.1)
Married	932 (25.8)	80 (26.1)	7 (26.9)
Other^b	228 (6.3)	22 (7.1)	0 (0.0)
Education
High school	3,202 (90.3)	284 (94.3)	25 (96.1)
College or higher	343 (9.7)	17 (5.6)	1 (3.9)
Military rank
Junior enlisted	3,020 (83.5)	262 (84.5)	25 (96.2)
Senior enlisted	598 (16.5)	48 (15.5)	1 (3.8)

American Indian/Alaskan Native, Asian/Pacific Islander, or other.

Divorced, separated, widowed, or other.

Denominators may vary because of missing data.

Chlamydia incidence rates

For all women, the mean follow-up time was 3.20 years (interquartile range [IQR] = 1.27–4.74 years). During the follow-up, 702 (19.40%) women had a diagnosis of chlamydia, yielding an incidence rate of 6.06 (95% CI = 5.63–6.53) cases per 100 person-years. Among women with one gonorrhea diagnosis, 488 had chlamydia, and its incidence rate was 4.57 cases per 100 person-years (Table 2). Among women with two gonorrhea diagnoses, 197 had a diagnosis of chlamydia, yielding an incidence rate of 23.40 cases per 100 person-years. Also, among women with three gonorrhea diagnoses, 17 had chlamydia with an incidence rate of 31.01 cases per 100 person-years. Analysis also revealed that the median time to diagnosis for chlamydia for women with two gonorrhea diagnosis was 2.39 years (IQR = 0.98–4.43), and 0.67 years (IQR = 0.20–1.96; ∼8 months) for women with three gonorrhea diagnoses.

Table 2.

Incidence Rates for Chlamydia by the Number of Gonorrhea Diagnoses Among U.S. Army Women

Feature	No. of women	No. (%) of women with subsequent chlamydia	Incidence rate (95% CI) per 100 person-years
Women with one gonorrhea diagnosis	3,618	488 (13.48)	4.57 (4.18–4.99)
Women with two gonorrhea diagnoses	310	197 (63.55)	23.40 (20.35–26.91)
Women with three gonorrhea diagnoses	29	17 (58.62)	31.01 (18.66–48.63)

95% CI, 95 percent confidence interval.

Hazard factor analysis

According to the PWP-GT analysis, the crude HR for chlamydia diagnosis for women with two gonorrhea diagnosis was 5.09 higher compared to women with one diagnosis (Table 3). After controlling for age, race/ethnicity, and marital status (model 1), the adjusted HR was 4.95. Subsequently, after controlling for a history of previous bacterial vaginosis, genital herpes simplex virus, and trichomoniasis (model 2), the adjusted HR was 4.81. Women with three gonorrhea diagnoses were 6.53 times more likely to be diagnosed with chlamydia compared to women with one gonorrhea diagnosis. After controlling for demographic variables (model 1) and other infections (model 2), the HR decreased to 5.76, and then to 5.28, respectively. All crude and adjusted HRs were significant at the 0.001 level. In addition, the Global test (p-value = 0.369) indicated that the proportional-hazards assumption was met in multiple regression analysis (model 2).

Table 3.

Unadjusted and Adjusted Hazard Ratios for Chlamydia by the Number of Gonorrhea Diagnoses Among U.S. Army Women

Feature	Crude HR (95% CI)	Model 1 Adjusted ^a HR (95% CI)	Model 2 Adjusted ^b HR (95% CI)
Women with one gonorrhea diagnosis	Ref.	Ref.	Ref.
Women with two gonorrhea diagnoses	5.09 (4.42–5.86)^c	4.95 (4.25–5.75)^c	4.81 (4.13–5.61)^c
Women with three gonorrhea diagnoses	6.53 (3.93–10.83)^c	5.76 (3.46–9.60)^c	5.28 (3.11–8.98)^c

Adjusted for age, race/ethnicity, and marital status.

Adjusted for age, race/ethnicity, marital status, bacterial vaginosis, genital herpes, and trichomoniasis.

p value <0.001.

HR, hazard ratio; Ref., reference for HR calculation.

Discussion

We found that among U.S. Army female personnel, the number of gonorrhea diagnoses was significantly associated with an increased hazard of chlamydia. This association undercovers the importance of repeat gonorrhea as a predisposing risk factor for subsequent chlamydia diagnosis.

The demographic characteristics of the female U.S. Army population in this study was representative of the young military population coming from throughout the United States and representing multiple, varied race/ethnicity backgrounds.

Our findings indicate a robust and significant relationship between the number of gonorrhea diagnoses and an elevated hazard of chlamydia diagnosis among U.S. Army women. To our knowledge, this is the first study investigating the effect of repeat gonorrhea events on the hazard of chlamydia. Most studies have only explored the first repeat gonorrhea event, ignoring the later gonorrhea events. On the other hand, the relationship found supports the hypothesis that chlamydia is frequently reported among women with gonorrhea. We cannot explain the biological mechanisms underlying this relationship, given that we had no data on other physiologic or behavioral risk factors. However, it is plausible to consider that individual risk factors such as use of hormonal contraception, engagement with new sexual partners, inconsistent condom use, and failure to treat sexual partners may explain this association.^12
–14

Notwithstanding our limitations, we were able to determine whether the association remained statistically significant after adjustment for surrogate markers of high-risk sexual behavior, such as diagnosis of bacterial vaginosis, genital herpes simplex virus, or trichomoniasis, which are also prevalent in the U.S. military.¹ Even after adjusting for these factors our hazard estimates for chlamydia were not meaningfully altered (model 2 in Table 3). Therefore, it would suggest that this association was independent of these factors. However, it is also possible that the small change between the crude and adjusted estimates is due to the low frequency of bacterial vaginosis, genital herpes simplex virus, or trichomoniasis in our study population. Given that, approximately less than 1% of women had these infections before the initial gonorrhea diagnosis.

Another important finding from this study was that the median time to chlamydia diagnosis decreased with an increasing number of gonorrhea episodes. That is, time to chlamydia diagnosis was shorter for women with two or more gonorrhea diagnoses than for women with one gonorrhea diagnosis. This information is vital for chlamydia screening programs. By observing a substantial hazard of chlamydia within a few months after having the third gonorrhea diagnosis, we suggest an early screening for chlamydia among this gonorrhea group to reduce the risk of long-term medical complication and prevent further transmission of both infections to their sexual partners. In the STI literature, there is no evidence on a consistent risk factor of subsequent infections for chlamydia or gonorrhea infection, with the exception of those having a new sexual partner.¹⁵ Therefore, our results support, to some extent, the idea of screening for chlamydia among gonorrhea “repeaters,” especially women with three gonorrhea diagnoses.

In addition to the lack of behavioral data for analysis, this study had other limitations. First, we had data on diagnoses only and the high rates of asymptomatic gonorrhea and chlamydia infections in women present challenges in obtaining accurate estimates of initial and repeat infections. Second, it is possible that some repeat diagnoses actually represent persistent infections, although the high efficacy of current treatments for gonorrhea may suggest a very low number of persistent infections. Third, due to stigma, fear of retribution or embarrassment, it is likely that some women seek care outside the military healthcare system, and therefore, they were not captured by the DMSS, resulting in missed gonorrhea diagnoses. Finally, our estimates might be biased due to the effect of short length of follow-up (3.20 years in this study). The magnitude of this bias is difficult to judge because each year, ∼9,750 new women enter and leave the U.S. Army.¹⁶ Despite these limitations, we feel that the timing and hazard estimates for chlamydia among gonorrhea “repeaters” represent a significant contribution of the STI literature.

In summary, this large population-based study revealed that among U.S. Army women, the hazard of chlamydia increases significantly with the number of gonorrhea diagnoses. In addition, the median time to chlamydia decreased with an increasing number of gonorrhea diagnoses. Results from our study have potential implications for public health practice and indicate the need of retesting for chlamydia (especially for those women with two or more gonorrhea diagnoses), which should be included in recommendations for STI control in the U.S. Army, in particular, if the goal is to detect women at high risk for chlamydia.

In addition, complementary military-based studies should determine what other biological and behavioral factors predispose women to sustain repeated gonorrhea diagnoses, as well as why there is such a strong association between gonorrhea “repeaters” and chlamydia. Data from such studies would be useful to develop interventions to prevent new chlamydia infections and repeat gonorrhea infections among U.S. Army women. Further research is also necessary to determine the hazard of gonorrhea among chlamydia repeaters among military women.

Footnotes

Acknowledgments

The authors thank Dr. Angelia Cost, at the Epidemiology and Analysis section of the AFHSB, for DMSS database extraction for this study, and Mr. Sebastian-Santiago for technical assistance. Also, we extend our thanks to Professors Bruce Hollingsworth and Sara Morris of the Division of Health Research, Lancaster University, UK, for their support during the development of this study. This study was funded by the U.S. Armed Forces Health Surveillance Branch and its Global Emerging Infectious Surveillance section (AFHSB-GEIS). The funder had no role in the study design, data analysis, or interpretation of findings, as well as in the writing and publication of this report.

Disclaimer

The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, the U.S. Government, or any organization listed. Some authors are employees of the U.S. government. This work was prepared as part of their official duties and, as such, there is no copyright to be transferred. This report was approved for publication by the Defense Health Agency, the Office of the Assistance Secretary of Defense for Health Affairs, as well as by the Department of Defense's Office of Prepublication and Security Review.

Author Disclosure Statement

No competing financial interests exist.

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